Design, Hemisynthesis, Characterization, Molecular Docking, and Dynamics Evaluation of Novel Totarol-1,2,3-Triazole Derivatives as Leishmaniasis and Toxoplasmosis Agents

Tropical parasitic diseases like leishmaniasis pose significant public health challenges, impacting millions of individuals globally. Current drug treatments for these diseases have notable drawbacks and side effects, underscoring the pressing need for new medications with improved selectivity and reduced toxicity. Through structural modifications of both natural and synthetic compounds using click chemistry, researchers have been able to produce derivatives showing promising activity against these parasites. In this study, 21 novel 1,2,3-triazole analogues of totarol were synthesized using O-propargylated totarol derivatives and substituted arylazide. These compounds were characterized through various analytical techniques, including ¹H NMR, ¹³C NMR, and HRMS. An x-ray crystallographic study of compounds 4 and 6 was carried out to fully establish the structure of the newly prepared totarol derivatives. All synthesized compounds were then screened in vitro for their antileishmanial activities against Leishmania major promastigotes, amastigotes, and Toxoplasma gondii tachyzoites Out of the tested analogues, six compounds (7c, 8b–e, and 9 g) displayed antileishmanial activity against L. major amastigotes with IC₅₀ 17.3, 14.2, 13.1 18.2 13.2 and 17.3 μg mL⁻¹ respectively, while only 8e gave antileishmanial activity against both promastigotes and amastigotes with IC₅₀ 11.7 and 13.2 μg mL⁻¹ respectively. Additionally, the presence of a nitro group was correlated with enhanced antileishmanial activity. Moreover, a molecular docking study was conducted, focusing on 8e, the most active antileishmanial compound, to elucidate its putative binding pattern at the active site of the selected leishmanial trypanothione reductase target.